2015 Fiscal Year Annual Research Report
Linking novel bioactive compounds to their targets and pathways using chemical genomics and morphological profiling
| Project/Area Number |
15H04483
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
BOONE CHARLES 国立研究開発法人理化学研究所, 環境資源科学研究センター, チームリーダー (70601342)
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| Co-Investigator(Kenkyū-buntansha) |
大矢 禎一 東京大学, 新領域創成科学研究科, 教授 (20183767)
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Keywords | chemical genomics / morphological profiling / yeast / target identification |
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| Outline of Annual Research Achievements |
We developed a novel high-throughput pipeline using various barcoded yeast mutant collections in a drug-hypersensitive genetic background. We designed a diagnostic pool of 310 non-essential deletion mutants to minimize the amount of compound required for screening and to maximize dynamic range. We efficiently and rapidly generate chemical genetic signatures for thousands of compounds via highly multiplexed next generation sequencing of DNA barcodes in the mutant strains. We then compared chemical genetic signatures with genome-wide synthetic lethal data to predict compound functionality at the biological process level. We applied this system to screen the NPDepo compound library. By FY2015, we assessed ~8,000 compounds for target specificity. We optimized calculation conditions to map predicted targets onto the global yeast genetic interaction network.
Further, we sought to develop and benchmark a novel image-profiling pipeline that links bioactive natural products to their cellular targets using small amount of bioactive compounds. We developed an integrated method that combines high-content microscopy and yeast non-essential deletion mutant collection in drug-hypersensitive background.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
We already screened ~8,000 NPDepo compounds using our novel high-throughput assay for measuring chemical genetic interactions. We optimized conditions for image acquisition using the drug hypersensitive host strain. Thus, we so far proceeded as we planned.
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| Strategy for Future Research Activity |
As we so far ~8,000 compounds from the NPDepo library, we will focus on the rest of the compounds (~2,000) to be assessed in FY2016. We will assemble the chemical genomic profiling data for 10,000 NPDepo compounds compared with genetic interaction data and will predict target proteins or target pathways of the compounds. We will also carry out an image-based screening for drug targets for super bioactive compounds among the NPDepo compounds using CalMorph.
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[Journal Article] Plant-derived antifungal agent poacic acid targets β-1,3-glucan.2015
Author(s)
Piotrowski JS, Okada H, Lu F, Li SC, Hinchman L, Ranjan A, Smith DL, Higbee AJ, Ulbrich A, Coon JJ, Deshpande R, Bukhman YV, McIlwain S, Ong IM, Myers CL, Boone C, Landick R, Ralph J, Kabbage M, Ohya Y.
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Journal Title
Proc Natl Acad Sci USA
Volume: 112
Pages: E1490-1497
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Controlling microbial contamination during hydrolysis of AFEX-pretreated corn stover and switchgrass: effects on hydrolysate composition, microbial response and fermentation.2015
Author(s)
Serate J, Xie D, Pohlmann E, Donald C Jr, Shabani M, Hinchman L, Higbee A, Mcgee M, La Reau A, Klinger GE, Li S, Myers CL, Boone C, Bates DM, Cavalier D, Eilert D, Oates LG, Sanford G, Sato TK, Dale B, Landick R, Piotrowski J, Ong RG, Zhang Y.
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Journal Title
Biotechnol Biofuels
Volume: 8
Pages: 180
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] 化学遺伝学と形態学のプロファイリング解析による細胞壁合成経路を標的にする抗真菌剤の探索2015
Author(s)
久保 佳蓮,岡田 啓希,Abraham Abrera,Sheena Li,Jeff Piotrowski,Chad Myers,八代田 陽子,Charlie Boone, 吉田 稔,長田 裕之,斎藤 臣雄,大矢 禎一
Organizer
第67回日本細胞生物学会大会
Place of Presentation
タワーホール船堀（東京都江戸川区）
Year and Date
2015-07-02 – 2015-07-02
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